Long-range Pitx2c enhancer–promoter interactions prevent predisposition to atrial fibrillation

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Abstract

Genome-wide association studies found that increased risk for atrial fibrillation (AF), the most common human heart arrhythmia, is associated with noncoding sequence variants located in proximity to PITX2. Cardiomyocyte-specific epigenomic and comparative genomics uncovered 2 AF-associated enhancers neighboring PITX2 with varying conservation in mice. Chromosome conformation capture experiments in mice revealed that the Pitx2c promoter directly contacted the AF-associated enhancer regions. CRISPR/Cas9-mediated deletion of a 20-kb topologically engaged enhancer led to reduced Pitx2c transcription and AF predisposition. Allele-specific chromatin immunoprecipitation sequencing on hybrid heterozygous enhancer knockout mice revealed that long-range interaction of an AF-associated region with the Pitx2c promoter was required for maintenance of the Pitx2c promoter chromatin state. Long-range looping was mediated by CCCTC-binding factor (CTCF), since genetic disruption of the intronic CTCF-binding site caused reduced Pitx2c expression, AF predisposition, and diminished active chromatin marks on Pitx2. AF risk variants located at 4q25 reside in genomic regions possessing long-range transcriptional regulatory functions directed at PITX2.

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Zhang, M., Hill, M. C., Kadow, Z. A., Suh, J. H., Tucker, N. R., Hall, A. W., … Martin, J. F. (2019). Long-range Pitx2c enhancer–promoter interactions prevent predisposition to atrial fibrillation. Proceedings of the National Academy of Sciences of the United States of America, 116(45), 22692–22698. https://doi.org/10.1073/pnas.1907418116

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